Submissions for variant NM_000277.3(PAH):c.561G>C (p.Trp187Cys)

dbSNP: rs62507336

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000668474	SCV002540147	likely pathogenic	Phenylketonuria	2021-10-31	reviewed by expert panel	curation	The c.561G>C (p.Trp187Cys) variant in PAH has been reported in a Japanese PKU patient (BH4 deficiency ruled out, genotype not reported; 21307867), and 2 Brazilian siblings with PKU (PMID: 30829006). It was detected with the pathogenic variant p.Val388Met in the siblings. PAH activity for this variant was 1% compared to wild type in a COS cell expression system (PMID: 9860305). This variant is absent in population databases, and predicted deleterious in multiple lines of computational evidence. In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4_moderate, PS3_supporting, PM2, PM3_supporting, PP3.
Counsyl	RCV000668474	SCV000793084	uncertain significance	Phenylketonuria	2017-08-02	criteria provided, single submitter	clinical testing
Invitae	RCV000668474	SCV003441287	pathogenic	Phenylketonuria	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 187 of the PAH protein (p.Trp187Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 102737). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 9860305, 17924342). This variant disrupts the p.Trp187 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32668217; BIOPKU http://www.biopku.org). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000668474	SCV004209714	likely pathogenic	Phenylketonuria	2023-01-04	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088986	SCV000119590	not provided	not provided		no assertion provided	not provided